60 E. B. Pasquale
to better understand the complex interplay between Eph receptors and other families of angiogenic factors. New therapeutic approaches for targeting Eph receptors and ephrins to promote or inhibit angiogenesis are undoubtedly also forthcoming.
Acknowledgments
The author thanks R. Bayer and N. Noren for helpful comments on the manuscript. The work in the author’s laboratory is supported by grants from the NIH and the Department of Defense.
References
1.Pasquale EB (2005). Eph receptor signalling casts a wide net on cell behaviour.
Nat Rev Mol Cell Biol 6: 462–475.
2.Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F (1987). A novel putative tyrosine kinase receptor encoded by the eph gene. Science 238: 1717–1720.
3.Eph-Nomenclature-Committee (1997). Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90: 403–404.
4.Bartley TD, Hunt RW, Welcher AA, et al. (1994). B61 is a ligand for the ECK receptor protein-tyrosine kinase. Nature 368: 558–560.
5.Pandey A, Shao H, Marks RM, Polverini PJ, Dixit VM (1995). Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science 268: 567–569.
6.Holmberg J, Clarke DL, Frisen J (2000). Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408: 203–206.
7.Palmer A, Zimmer M, Erdmann KS, et al. (2002). EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Mol Cell 9: 725–737.
8.Song J (2003). Tyrosine phosphorylation of the well packed ephrinB cytoplasmic beta-hairpin for reverse signaling. Structural consequences and binding properties. J Biol Chem 278: 24714–24720.
9.Cowan CA, Henkemeyer M (2001). The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413: 174–179.
10.Pasquale EB (2004). Eph-ephrin promiscuity is now crystal clear. Nat Neurosci 7: 417–418.
11.Miao H, Burnett E, Kinch M, Simon E, Wang B (2000). Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol 2: 62–69.
12.Dohn M, Jiang JY, Chen XB (2001). Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis. Oncogene 20: 6503–6515.
13.Stein E, Lane AA, Cerretti DP, et al. (1998). Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, assembly responses. Genes Dev 12: 667–678.
EPH Receptors and Ephrins 61
14.Brantley DM, Cheng N, Thompson EJ, et al. (2002). Soluble Eph A, receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21: 7011–7026.
15.Dobrzanski P, Hunter K, Jones-Bolin S, et al. (2004). Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res 64: 910–919.
16.Sarma V, Wolf FW, Marks RM, Shows TB, Dixit VM (1992). Cloning of a novel tumor necrosis factor-alpha-inducible primary response gene that is differentially expressed in development and capillary tube-like formation in vitro. J Immunol 148: 3302–3312.
17.Daniel TO, Stein E, Cerretti DP, et al. (1996). ELK and LERK-2 in developing kidney and microvascular endothelial assembly. Kidney Int — Suppl 57: S73–81.
18.Myers C, Charboneau A, Boudreau N (2000). Homeobox B3 promotes capillary morphogenesis and angiogenesis. J Cell Biol 148: 343–351.
19.Cheng N, Brantley DM, Liu H, et al. (2002). Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res 1: 2–11.
20.Brantley-Sieders DM, Caughron J, Hicks D, et al. (2004). EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J Cell Sci 117: 2037– 2049.
21.Ogawa K, Pasqualini R, Lindberg RA, et al. (2000). The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19: 6043–6052.
22.Pandey A, Lazar DF, Saltiel AR, Dixit VM (1994). Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity. J Biol Chem 269: 30154–30157.
23.Ogita H, Kunimoto S, Kamioka Y, et al. (2003). EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells. Circ Res 93: 23–31.
24.Deroanne C, Vouret-Craviari V, Wang B, Pouyssegur J (2003). EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway. J Cell Science 116: 1367–1376.
25.Adams RH, Wilkinson GA, Weiss C, et al. (1999). Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/ venous domains, vascular morphogenesis, sprouting angiogenesis. Genes Dev 13: 295–306.
26.Kim I, Ryu YS, Kwak HJ, et al. (2002). EphB ligand, ephrinB2, suppresses the VEGFand angiopoietin 1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. FASEB J 16: 1126–1128.
27.Sawai Y, Tamura S, Fukui K, et al. (2003). Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization. J Hepatol 39: 991–996.
28.Steinle JJ, Meininger CJ, Forough R, et al. (2002). Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 277: 43830–43835.
29.Huynh-Do U, Stein E, Lane AA, et al. (1999). Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins. EMBO J 18: 2165–2173.
62E. B. Pasquale
30.Hayashi S, Asahara T, Masuda H, Isner JM, Losordo DW (2005). Functional ephrin-B2 expression for promotive interaction between arterial and venous vessels in postnatal neovascularization. Circulation 111: 2210–2218.
31.Becker E, Huynh-Do U, Holland S, et al. (2000). Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol Cell Biol 20: 1537–1545.
32.Vindis C, Teli T, Cerretti DP, Turner CE, Huynh-Do U (2004). EphB1-mediated cell migration requires the phosphorylation of paxillin at Tyr-31/Tyr-118. J Biol Chem 279: 27965–27970.
33.Vindis C, Cerretti DP, Daniel TO, Huynh-Do U (2003). EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol 162: 661–671.
34.Nagashima K, Endo A, Ogita H, et al. (2002). Adaptor protein crk is required for Ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells. Mol Biol Cell 13: 4231–4242.
35.Maekawa H, Oike Y, Kanda S, et al. (2003). Ephrin-B2 induces migration of endothelial cells through the phosphatidylinositol-3 kinase pathway and promotes angiogenesis in adult vasculature. Arterioscler Thromb Vasc Biol 23: 2008–2014.
36.Hamada K, Oike Y, Ito Y, et al. (2003). Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells. Arterioscler Thromb Vasc Biol 23: 190–197.
37.Fuller T, Korff T, Kilian A, Dandekar G, Augustin HG (2003). Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci 116: 2461–2470.
38.Noren NK, Lu M, Freeman AL, Koolpe M, Pasquale EB (2004). Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc Natl Acad Sci USA 101: 5583–5588.
39.Adams RH, Diella F, Hennig S, et al. (2001). The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 104: 57–69.
40.Huynh-Do U, Vindis C, Liu H, et al. (2002). Ephrin-B1 transduces signals to activate integrin-mediated migration, attachment and angiogenesis. J Cell Sci 115: 3073–3081.
41.Bruhl T, Urbich C, Aicher D, et al. (2004). Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation. Circ Res 94: 743–751.
42.Steinle JJ, Meininger CJ, Chowdhury U, Wu G, Granger HJ (2003). Role of ephrin B2 in human retinal endothelial cell proliferation and migration. Cell Signal 15: 1011–1017.
43.le Noble F, Moyon D, Pardanaud L, et al. (2004). Flow regulates arterialvenous differentiation in the chick embryo yolk sac. Development 131: 361–375.
44.Dixit VM, Green S, Sarma V, et al. (1990). Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J Biol Chem 265: 2973–2978.
EPH Receptors and Ephrins 63
45.Holzman LB, Marks RM, Dixit VM (1990). A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein. Mol Cell Biol 10: 5830–5838.
46.Cheng N, Chen J (2001). Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPK– and SAPK/JNKdependent but nuclear factor-kappa B-independent mechanism. J Biol Chem 276: 13771–13777.
47.Abdollahi A, Hahnfeldt P, Maercker C, et al. (2004). Endostatin’s antiangiogenic signaling network. Mol Cell 13: 649–663.
48.Cheng N, Brantley D, Fang WB, et al. (2003). Inhibition of VEGFdependent multistage carcinogenesis by soluble EphA receptors. Neoplasia 5: 445–456.
49.Mukouyama YS, Shin D, Britsch S, Taniguchi M, Anderson DJ (2002). Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 109: 693–705.
50.Masood R, Xia G, Smith DL, et al. (2005). Ephrin B2 expression in Kaposi sarcoma is induced by human herpesvirus type 8: phenotype switch from venous to arterial endothelium. Blood 105: 1310–1318.
51.Shin D, Garcia-Cardena G, Hayashi SI, et al. (2001). Expression of ephrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, marks subsets of microvessels at sites of adult neovascularization. Dev Biol 230: 139–150.
52.Visconti RP, Richardson CD, Sato TN (2002). Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). PNAS 99: 8219–8224.
53.Rossant J, Howard L (2002). Signaling pathways in vascular development. Annu Rev Cell Dev Biol 18: 541–573.
54.Zhong TP, Childs S, Leu JP, Fishman MC (2001). Gridlock signalling pathway fashions the first embryonic artery. Nature 414: 216–220.
55.Yuan K, Hong TM, Chen JJ, Tsai WH, Lin MT (2004). Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis. Blood 104: 1025–1033.
56.Brantley-Sieders DM, Fang WB, Hicks DJ, et al. (2005). Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J 19: 1884–1886.
57.Depaepe V, Suarez-Gonzalez N, Dufour A, et al. (2005). Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435: 1244–1250.
58.Wang Z, Cohen K, Shao Y, et al. (2004). Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, blood vessels. Blood 103: 100–109.
59.Wang Z, Miura N, Bonelli A, et al. (2002). Receptor tyrosine kinase, EphB4 (HTK), accelerates differentiation of select human hematopoietic cells. Blood 99: 2740–2747.
60.McBride JL, Ruiz JC (1998). Ephrin-A1 is expressed at sites of vascular development in the mouse. Mech Dev 77: 201–204.
64E. B. Pasquale
61.Flenniken AM, Gale NW, Yancopoulos GD, Wilkinson DG (1996). Distinct and overlapping expression patterns of ligands for Eph-related receptor tyrosine kinases during mouse embryogenesis. Dev Biol 179: 382–401.
62.Takahashi H, Ikeda T (1995). Mol cloning and expression of rat and mouse B61 gene: implications on organogenesis. Oncogene 11: 879–883.
63.Stadler HS, Higgins KM, Capecchi MR (2001). Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13 mutant limbs. Development 128: 4177–4188.
64.Wang HU, Chen ZF, Anderson DJ (1998). Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93: 741–753.
65.Gerety SS, Wang HU, Chen ZF, Anderson DJ (1999). Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4: 403–414.
66.Othman-Hassan K, Patel K, Papoutsi M, et al. (2001). Arterial identity of endothelial cells is controlled by local cues. Dev Biol 237: 398–409.
67.Goettsch W, Augustin HG, Morawietz H (2004). Down-regulation of endothelial ephrinB2 expression by laminar shear stress. Endothelium 11: 259–265.
68.Claxton S, Fruttiger M (2005). Oxygen modifies artery differentiation and network morphogenesis in the retinal vasculature. Dev Dyn 233: 822–828.
69.Hall SM, Hislop AA, Haworth SG (2002). Origin, differentiation, maturation of human pulmonary veins. Am J Respir Cell Mol Biol 26: 333–340.
70.Risau W (1997). Mechanisms of angiogenesis. Nature 386: 671–674.
71.Oike Y, Ito Y, Hamada K, et al. (2002). Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells. Blood 100: 1326–1333.
72.Gerety SS, Anderson DJ (2002). Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129: 1397–1410.
73.Makinen T, Adams RH, Bailey J, et al. (2005). PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19: 397–410.
74.Cowan CA, Yokoyama N, Saxena A, et al. (2004). Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development. Dev Biol 271: 263–271.
75.Zhang XQ, Takakura N, Oike Y, et al. (2001). Stromal cells expressing ephrin-B2 promote the growth and sprouting of ephrin-B2(+) endothelial cells. Blood 98: 1028–1037.
76.Helbling PM, Saulnier DM, Brandli AW (2000). The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 127: 269–278.
77.Hafner C, Schmitz G, Meyer S, et al. (2004). Differential gene expression of Eph receptors and Ephrins in benign human tissues and cancers. Clin Chem 50: 490–499.
78.Gale NW, Baluk P, Pan L, et al. (2001). Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol 230: 151–160.
EPH Receptors and Ephrins 65
79.Red-Horse K, Kapidzic M, Zhou Y, et al. (2005). EPHB4 regulates chemokineevoked trophoblast responses: a mechanism for incorporating the human placenta into the maternal circulation. Development 132: 4097–4106.
80.Yuan K, Jin YT, Lin MT (2000). Expression of Tie-2, angiopoietin-1, angiopoietin–2, ephrinB2 and EphB4 in pyogenic granuloma of human gingiva implicates their roles in inflammatory angiogenesis. J Periodontal Res 35: 165–171.
81.Vihanto MM, Plock J, Erni D, et al. (2005). Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin. FASEB J 19: 1689–1691.
82.Suenobu S, Takakura N, Inada T, et al. (2002). A role of EphB4 receptor and its ligand, ephrin-B2, in erythropoiesis. Biochem Biophys Res Commun 293: 1124–1131.
83.Carmeliet P, Jain RK (2000). Angiogenesis in cancer and other diseases. Nature 407: 249–257.
84.Hess AR, Seftor EA, Gardner LM, et al. (2001). Molecular regulation of tumor cell vasculogenic mimicry by tyrosine phosphorylation: role of epithelial cell kinase (Eck/EphA2). Cancer Res 61: 3250–3255.
85.Kataoka H, Igarashi H, Kanamori M, et al. (2004). Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer. Cancer Sci 95: 136–141.
86.Papoutsi M, Othman-Hassan K, Christ B, Patel K, Wilting J (2002). Development of an arterial tree in C6 gliomas but not in A375 melanomas. Histochem Cell Biol 118: 241–249.
87.Martiny-Baron G, Korff T, Schaffner F, et al. (2004). Inhibition of tumor growth and angiogenesis by soluble EphB4. Neoplasia 6: 248–257.
88.Andres AC, Munarini N, Djonov V, et al. (2003). EphB4 receptor tyrosine kinase transgenic mice develop glomerulopathies reminiscent of aglomerular vascular shunts. Mech Dev 120: 511–516.
89.Liu W, Jung YD, Ahmad SA, et al. (2004). Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer. British J Cancer 90: 1620–1626.
90.Zamora DO, Davies MH, Planck SR, Rosenbaum JT, Powers MR (2005). Soluble forms of EphrinB2 and EphB4 reduce retinal neovascularization in a model of proliferative retinopathy. Invest Ophthalmol Vis Sci 46: 2175–2182.
91.Murai KK, Nguyen LN, Koolpe M, et al. (2003). Targeting the EphA4 receptor in the nervous system with biologically active peptides. Mol Cell Neurosci 24: 1000–1011.
92.Koolpe M, Burgess R, Dail M, Pasquale EB (2005). EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J Biol Chem 280: 17301–17311.
93.Xia G, Kumar SR, Masood R, et al. (2005). Up-Regulation of EphB4 in Mesothelioma and its biological significance. Clin Cancer Res 11: 4305–4315.
94.Xia G, Kumar SR, Masood R, et al. (2005). EphB4 expression and biological significance in prostate cancer. Cancer Res 65: 4623–4632.
95.Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE (2004). EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma. Oncogene 23: 1448–1456.
96.Koolpe M, Dail M, Pasquale EB (2002). An ephrin mimetic peptide that selectively targets the EphA2 receptor. J Biol Chem 277: 46974–46979.
66E. B. Pasquale
97.Carles-Kinch K, Kilpatrick KE, Stewart JC, Kinch MS (2002). Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior. Cancer Res 62: 2840–2847.
98.Zisch AH, Zeisberger SM, Ehrbar M, et al. (2004). Engineered fibrin matrices for functional display of cell membrane-bound growth factor–like activities: study of angiogenic signaling by ephrin-B2. Biomaterials 25: 3245–3257.